How to Supplement Iron in Patients with Renal Anemia

Abstract

Iron deficiency is a major cause of hyporesponsiveness to erythropoiesis-stimulating agents (ESAs) and is often observed in chronic kidney disease (CKD) patients with anemia. With iron supplementation, ESA doses can be decreased, resulting in lower treatment costs and possibly lower cardiovascular risks that are associated with high-dose ESA therapy. The 2012 Kidney Disease: Improving Global Outcomes Guideline specified ferritin ≤500 ng/ml and transferrin saturation (TSAT) ≤30% as thresholds of iron parameters for CKD patients. However, long-term safety (in terms of mortality, cardiovascular/infection risk and tissue deposition) of high-dose intravenous iron supplementation with such high target levels of ferritin/TSAT has not been confirmed. Recently, there has been increase in the use of intravenous iron and average ferritin levels in dialysis patients in the United States. Clinical trials conducted so far have been underpowered to conclusively establish the long-term safety of intravenous iron supplementation. Results from observational studies are conflicting, and many experimental studies have even shown negative effects of intravenous iron. Clearly, randomized clinical trials are urgently needed, studying various doses of intravenous iron, with sufficient patient numbers and longer observation periods, to investigate mortality, cardiovascular effects and infection risks of this treatment. Until the long-term safety of iron supplementation at high doses is established, a more prudent decision on iron supplementation with lower target levels of ferritin/TSAT seems reasonable, in light of the decades of experience with ESA that has shown that definitive clinical outcomes have been dissociated from surrogate outcomes (especially hemoglobin concentration).

Risk of iron overload with chronic indiscriminate use of intravenous iron products in ESRD and IBD populations

“…Some recent radiological and epidemiological findings have led to editorials and position papers highlighting the potential dangers of the excessive use of IV iron products in CKD patients and the inadequacy of guidelines proposed in 2012 by the KDIGO, the iron biomarker targets set by the KDOQI in 2006 and the EDTA-ERA statement in 2009 for their ability to protect ESRD patients from iron overload [120,122,123]. Moreover recent reviews on anaemia and iron therapy in CKD have also presented a more balanced view, emphasizing the benefits and also describing the potential risks, including iron overload [124,125,126,127].…”

Iatrogenic Iron Overload in Dialysis Patients at the Beginning of the 21st Century

“…The Dialysis Advisory Group of the American Society of Nephrology has engaged in a profound and frank debate that has greatly contributed to understanding and overcoming this possible ongoing epidemic of iron overload in dialysis patients [ 9 , 20 ]. Recent reviews of anemia and iron therapy in CKD, published in hematological and nephrology journals, have given a more balanced view, emphasizing not only the benefits but also the risks, including the danger of iron overload [ 95 – 98 ].…”

Therapeutic Implications of Ferroptosis in Renal Fibrosis

“…However, as mentioned above, a key feature of ferroptosis is intracellular overload iron and catalysis of lipid peroxidation, which are both common and worsen in CKD with disease progression ( Naito et al, 2015 ). In addition, proactive high-dose iron supplementation due to renal anemia also led to renal iron toxicity ( Tanaka and Tanaka, 2015 ; van Raaij et al, 2018b ). Thus, diverse chronic kidney disease creates an appropriate condition for the occurrence of ferroptosis.…”